Transdermal drug delivery systems have become an important method of administering drugs. Transdermal delivery systems are specially suited for delivering controlled quantities of a drug or other active substances to a patient over an extended period of time. In these controlled delivery systems, active agent is released by permeation from the interior of the patch to the surrounding medium.
Novel drug delivery dosage forms, such as transdermal or topical, have acquired widened popularity in recent years. A few of the potential benefits offered by transdermal systems include minimization of the side effects often associated with the conventional oral route of drug delivery and a reduced frequency of dose administration. However, the development of transdermal formulations and patch configurations for percutaneous delivery of an active agent requires extensive in vitro permeation testing to assess the feasibility of delivering such an agent at efficacious dosages through the skin. The primary goal of in vitro permeation studies is the prediction of skin permeation in vivo.
There are several approaches to classifying transdermal systems. One is by drug release mechanism, another is with regard to system design. According to the system design method, one considers whether a given transdermal system is considered to be membrane controlled, system controlled, a matrix or a monolith. See Cleary, GW. Cosmetics & Toiletries 106:97 (1991). In following the latter classification method, there are four basic transdermal designs currently on the market. One is a semi-solid design in which a semi-solid amorphous ointment, cream, lotion or viscous gel is applied directly to the skin. Oftentimes, semi-solid ointments, gels, creams, foams, etc., are considered separately from transdermal systems as topical delivery systems. A second type of transdermal system is the liquid form, fill, and seal laminate design, which typically consists of (progressing from the surface of the device most distal to the skin of the wearer) a drug impermeable backing, a liquid-filled drug layer, a structural or modulator layer (such as a membrane), and a skin contact adhesive. A third type of design utilizes a peripheral adhesive and consists of a backing, a skin contact adhesive (which extends past the periphery of the active releasing area of the patch to form a peripheral adhesive portion), an anchor or barrier layer, and a drug layer. The fourth type of design (of which there are numerous variations) is the solid state laminate design. The simplest solid state design patch consists of a backing and a skin contact adhesive layer which incorporates drug. Another variation includes the insertion of an additional drug layer between the backing and the drug-adhesive layer. A third solid state laminate design consists of a backing, an anchor/drug layer, a structural/modulator layer, and a skin contact adhesive. Suitable materials for use in fabrication of the various patch layers will be obvious to one skilled in the art. See for example U.S. Pat. Nos. 3,598,122; 4,286,592, and pending U.S. patent application, Ser. No. 08/060,907. For a detailed discussion of transdermal delivery systems, see J. Hadgraft and R. H. Guy, "Transdermal Drug Delivery, Developmental Issues and Research Initiatives", Marcel Dekker, Inc., 1989, especially chapter 12, the disclosure of which is incorporated by reference.
In developing a transdermal delivery system, one must also assess the utility of different drug vehicles in the percutaneous absorption process, namely the partitioning of the active agent into the stratum corneum. The stratum corneum is the primary diffusional barrier toward drugs; most drugs are not able to permeate the skin at a useful rate by themselves and require a skin permeation agent or enhancer to increase the skin's permeability to drug. A tremendous number of permeation enhancers are known in the art; for a review of the transdermal enhancer patent literature, see G. C. Santus and R. W. Baker, J. Controlled Release, 1993, 25, 1-20, the contents of which are expressly incorporated by reference.
In determining the feasibility of delivering an active agent transdermally, or in engineering an appropriate release profile, one must consider both the physical and chemical properties of the drug as well as a choice of suitable system components, including permeation enhancers. Drug delivery through the skin may be affected by drug solubility, choice of solvent, polymer diffusion properties, thickness of layers, membrane selection, and so forth. Therefore, based on the vast number of parameters to be considered and evaluated in the course of development of a trandermal system, one can appreciate the need for an apparatus which provides a means for simultaneously conducting large numbers of permeation tests, in an efficient and reproducible fashion, and which requires a minimum amount of sample for each test.
In general, such a diffusion testing apparatus would find applicability in any area in which the investigation of transport properties through a barrier is of interest. Such an apparatus would be particularly useful to assess the transport properties and viability of delivering a potential drug candidate through various epithelial barriers, such as those which constitute the intestinal, rectal, buccal, sublingual, nasal, and ophthalmic mucosa, as well as endothelial barriers. Model in vitro cell culture systems of various-epithelial and endothelial barriers have been used to successfully mimic biological barriers. For a review of in vitro cell culture models used in transport studies, see Audus, et al., Pharmaceutical Research, 1990, 7 (5), 435-451, the contents of which is expressly incorporated by reference.